Large epidemiological and clinical studies have provided convincing evidences for healthy promoting effects of natural carotenoids (1-3). Positive effects of natural carotenoids on human health primarily attributed to their provitamin and antioxidant activities (1-4). Natural carotenoids β-carotene, lycopene, lutein, astaxanthin and fucoxanthin are well known for their anti-cancer and superior free radicals scavenging properties (1-5). Recent studies have revealed that some carotenoids possess much more specific and unique pharmacological effects. For example, it has been reported that fucoxanthin, a carotenoid specific to brown marine vegetables, shows anti-obesity and thermogenic effects (6-8). According to the report, fucoxanthin upregulates the expression of uncoupling protein UCP1 gene in white adipose tissue (WAT), thus contributing to reduction of visceral fat (6, 8). It was demonstrated that fucoxanthin reduced WAT in wistar rats and obese KK-Ay mice (6-8). Fucoxanthin-induced UCP1 expression in WAT stimulates oxidation of fatty acids (6-8). UCP proteins may also be involved in regulation of body weight and obesity (12-14). The induced overexpression of UCP proteins can become a new target for development of anti-obesity drugs (13, 14).
The anti-obesity properties of fucoxanthin and its metabolite fucoxanthinol are associated with their ability to inhibit the activity of glycerol-3-phosphate dehydrogenase enzyme (7). In addition, fucoxanthin and fucoxanthinol down regulates peroxisome proliferator-activated receptor γ (PPARγ), which regulates adipogenic gene expression (7) and contributes to anti-obesity effects.
Fatty acids with conjugated double bonds acid have attracted considerable attention because of its potentially anti-obesity effects (15-17). Conjugated linoleic acids (CLAs) have been shown to reduce body fat in rodents and humans (18-20). Conjugated linoleic acid may reduce body fat mass and increase lean body mass in healthy overweight adults (18-21). Conjugated linolenic acids (CLNAs), another conjugated fatty acids, may reduce adipose tissues in rats (22). CLNAs have been suggested to modulate body fat and triacylglycerol metabolism in a manner different from that of CLAs (22), although the exact mechanism of the anti-obese action of CLAs and CLNAs remains unknown.
Punicic acid (9cis, 11trans, 13cis-conjugated linolenic acid; 9c, 11t, 13c-CLNA), a conjugated linolenic acid, is a primary fatty acid found in pomegranate seed oil (23-26). Dietary pomegranate seed oil rich in punicic acid alleviates accumulation of liver triacylglycerol (TGs) in obese, hyperlipidemic OLETF rats (26). The diet supplemented with 5% pomegranate seed oil resulted in a significant reduction of WAT weight (by 27%) compared with the feeding of control diet in OLETF rats, whereas feeding of 1% pomegranate seed oil diet didn't produce significant anti-obese effect (26). Thus, these results indicate that the anti-obesity effect of punicic acid is strongly dose-depending phenomenon. Reportedly, anti-obesity effect of punicic acid is related to its ability to suppress delta-9 desaturation in vivo, and the alleviation of hepatic TGs accumulation by dietary punicic acid is attributable to the suppression of delta-9 desaturation in OLETF rats (26).
Therefore, punicic acid possesses anti-obesity properties that can prevent the visceral fat accumulation and reduce liver fat in obese subjects. The accumulation of TGs in the liver is a primary metabolic factor that contributes to development of nonalcoholic fatty liver disease (NAFLD) that plays a major role in the development of insulin-resistance and obesity.
The term NAFLD used herein refers to a spectrum of hepatic pathology that resembles alcoholic liver disease, but appears in individuals who have low or negligible alcohol consumption (29, 30). The prevalence of NAFLD among examined overall population is approximately 9% in Western countries (31) and 1.2% in Japan (32). In Western countries the prevalence of NAFLD among obese subjects ranges from 23-31 percent (33, 34). The majority of patients with NAFLD is also overweight and obese, and has underlying insulin resistance (35). NAFLD is one of the main causes of chronic liver disease and it is believed to be the hepatic component of the metabolic syndrome. Its central features include obesity, hyperinsulinemia, peripheral insulin resistance, diabetes, dyslipidemia, and hypertension (36, 37). The severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance in both obese and non obese subjects, suggesting that hepatic fat infiltration in NAFLD may be influenced by visceral fat accumulation regardless of body mass index (37).
Surprisingly enough the pathogenesis of NAFLD is commonly encountered in acute starvation (fast weight loss), carbohydrate overload, protein-energy malnutrition, and corticosteroid therapy; thus, these are common mechanism for the accumulation of TGs in the liver. The gender also plays an important role in the development of NAFLD because it is more prevalent among women than men, although there is not sufficient evidence as to whether female hormones that may cause NAFLD are more prevalent in women (38, 39). NAFLD is seen most frequently in females who are morbidly obese and have had jejunal bypass surgery. Such females have an elevated level of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (40, 41). Although weight loss was often correlated with reduction of NAFLD conditions, the effect of weight loss on fatty liver disease is not consistent (42-45).
Although edible brown marine vegetables containing 0.01-0.02% fucoxanthin and pomegranate have a long and safe history of human consumption, the effect of concentrated fucoxanthin and pomegranate seed oil on a treatment of liver fat and body fat, a stimulation of muscle protein synthesis, a reduction of blood pressure, an increase of the energy expenditure rate, a reduction of inflammatory C-reactive proteins and a reduction of plasma transaminase enzymes has not yet been studied. Furthermore, although both fucoxanthin and punicic acid have shown described pharmacological effects, any synergistic effect on a treatment of liver fat and body fat, a stimulation of muscle protein synthesis, a reduction of blood pressure, an increase of the energy expenditure rate, a reduction of inflammatory C-reactive proteins and a reduction of plasma transaminase enzymes when supplemented together has not been discovered.
Therefore, it would be useful to provide compositions for a medicinal or health effect of a treatment of liver fat and body fat, a stimulation of muscle protein synthesis, a reduction of blood pressure, an increase of the energy expenditure rate, a reduction of inflammatory C-reactive proteins and a reduction of plasma transaminase enzymes, comprising an effective amount of fucoxanthin alone or in combination with pomegranate seed oil, a pharmaceutically acceptable salt, a prodrug thereof, or a salt of the prodrug.